Abstract
Alzheimer’s disease (AD) is a common age-related neurodegenerative disorder that is characterized by progressive cognitive decline. The deficits in cognition and attentional processing that are observed clinically in AD are linked to impaired function of cholinergic neurons that release the neurotransmitter acetylcholine (ACh). The high-affinity choline transporter (CHT) is present at the presynaptic cholinergic nerve terminal and is responsible for the reuptake of choline produced by hydrolysis of ACh following its release. Disruption of CHT function leads to decreased choline uptake and ACh synthesis, leading to impaired cholinergic neurotransmission. We report here that cell-derived β-amyloid peptides (Aβ) decrease choline uptake activity and cell surface CHT protein levels in SH-SY5Y neural cells. Moreover, we make the novel observation that the amount of CHT protein localizing to early endosomes and lysosomes is decreased significantly in cells that have been treated with cell culture medium that contains Aβ peptides released from neural cells. The Aβ-mediated loss of CHT proteins from lysosomes is prevented by blocking lysosomal degradation of CHT with the lysosome inhibitor bafilomycin A1 (BafA1). BafA1 also attenuated the Aβ-mediated decrease in CHT cell surface expression. Interestingly, however, lysosome inhibition did not block the effect of Aβ on CHT activity. Importantly, neutralizing Aβ using an anti-Aβ antibody directed at the N-terminal amino acids 1–16 of Aβ, but not by an antibody directed at the mid-region amino acids 22–35 of Aβ, attenuates the effect of Aβ on CHT activity and trafficking. This indicates that a specific N-terminal Aβ epitope, or specific conformation of soluble Aβ, may impair CHT activity. Therefore, Aβ immunotherapy may be a more effective therapeutic strategy for slowing the progression of cognitive decline in AD than therapies designed to promote CHT cell surface levels.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disorder defined by progressive and irreversible cognitive decline
Inhibition of choline transporter (CHT) function by Aβ peptides was blocked by an antibody directed at the N-terminal amino acids 1–16 of Aβ, but not by an antibody directed at the mid-region amino acids 22–35 of Aβ
Aβ peptides were recovered from conditioned medium (CM)-vector and CM-APPSwe by immunoprecipitation using either anti-HA antibody as a negative control, anti-Aβ antibody directed at amino acids 1–16 at the N-terminus of Aβ or anti-Aβ antibody directed at amino acids 22–35 in the mid-region of Aβ
Summary
Alzheimer’s disease (AD) is a neurodegenerative disorder defined by progressive and irreversible cognitive decline. Cholinergic transmission promotes the non-amyloidogenic α-cleavage of APP through ACh stimulation of muscarinic receptors (Nitsch et al, 1992), while APP plays a role in cholinergic neurons by regulating the presynaptic localization of CHT proteins and their internalization from the cell surface (Wang et al, 2007) It has been shown in experiments using synthetic preparations of Aβ peptides that oligomeric Aβ can negatively regulate ACh synthesis and release by inhibiting high-affinity choline uptake (Pedersen et al, 1996; Auld et al, 1998; Kar et al, 1998; Parikh et al, 2014); one study reported enhanced choline uptake activity in synaptosomes and neural cells exposed acutely to oligomeric Aβ1–42, but links this to reduced ACh release (Bales et al, 2006). Accumulation of Aβ peptides in brain may inhibit CHT activity, decreasing ACh synthesis and impairing cholinergic transmission
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